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Gene Expression Signatures Associated With Survival Times of Pediatric Patients With Biliary Atresia Identify Potential Therapeutic Agents.

ABSTRACT: BACKGROUND & AIMS:Little is known about the factors that affect outcomes of patients with biliary atresia and there are no medical therapies that increase biliary drainage. METHODS:Liver biopsies and clinical data were obtained from infants with cholestasis and from children without liver disease (controls); messenger RNA (mRNA) was isolated, randomly assigned to discovery (n = 121) and validation sets (n = 50), and analyzed by RNA sequencing. Using the Superpc R package followed by Cox regression analysis, we sought to identify gene expression profiles that correlated with survival without liver transplantation at 24 months of age. We also searched for combinations of gene expression patterns, clinical factors, and laboratory results obtained at diagnosis and at 1 and 3 months after surgery that associated with transplant-free survival for 24 months of age. We induced biliary atresia in BALB/c mice by intraperitoneal administration of Rhesus rotavirus type A. Mice were given injections of the antioxidants N-acetyl-cysteine (NAC) or manganese (III) tetrakis-(4-benzoic acid)porphyrin. Blood and liver tissues were collected and analyzed by histology and immunohistochemistry. RESULTS:We identified a gene expression pattern of 14 mRNAs associated with shorter vs longer survival times in the discovery and validation sets (P < .001). This gene expression signature, combined with level of bilirubin 3 months after hepatoportoenterostomy, identified children who survived for 24 months with an area under the curve value of 0.948 in the discovery set and 0.813 in the validation set (P < .001). Computer models correlated a cirrhosis-associated transcriptome with decreased times of transplant-free survival; this transcriptome included activation of genes that regulate the extracellular matrix and numbers of activated stellate cells and portal fibroblasts. Many mRNAs expressed at high levels in liver tissues from patients with 2-year transplant-free survival had enriched scores for glutathione metabolism. Among mice with biliary atresia given injections of antioxidants, only NAC reduced histologic features of liver damage and serum levels of aminotransferase, gamma-glutamyl transferase, and bilirubin. NAC also reduced bile duct obstruction and liver fibrosis and increased survival times. CONCLUSIONS:In studies of liver tissues from infants with cholestasis, we identified a 14-gene expression pattern that associated with transplant-free survival for 2 years. mRNAs encoding proteins that regulate fibrosis genes were increased in liver tissues from infants who did not survive for 2 years, whereas mRNAs that encoded proteins that regulate glutathione metabolism were increased in infants who survived for 2 years. NAC reduced liver injury and fibrosis in mice with biliary atresia, and increased survival times. Agents such as NAC that promote glutathione metabolism might be developed for treatment of biliary atresia.

SUBMITTER: Luo Z

PROVIDER: S-EPMC6756963 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Gene Expression Signatures Associated With Survival Times of Pediatric Patients With Biliary Atresia Identify Potential Therapeutic Agents.

Luo Zhenhua Z Shivakumar Pranavkumar P Mourya Reena R Gutta Sridevi S Bezerra Jorge A JA

Gastroenterology 20190619 4

<h4>Background & aims</h4>Little is known about the factors that affect outcomes of patients with biliary atresia and there are no medical therapies that increase biliary drainage.<h4>Methods</h4>Liver biopsies and clinical data were obtained from infants with cholestasis and from children without liver disease (controls); messenger RNA (mRNA) was isolated, randomly assigned to discovery (n = 121) and validation sets (n = 50), and analyzed by RNA sequencing. Using the Superpc R package followed ...[more]

PMID: 31228442

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Project description:No systematic review to date has examined histopathological parameters in relation to native liver survival in children who undergo the Kasai operation for biliary atresia (BA). A systematic review and meta-analysis is presented, comparing the frequency of native liver survival in peri-operative severe vs. non-severe liver fibrosis cases, in addition to other reported histopathology parameters. Records were sourced from MEDLINE, Embase, and CENTRAL databases. Studies followed the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines and compared native liver survival frequencies in pediatric patients with evidence of severe vs. non-severe liver fibrosis, bile duct proliferation, cholestasis, lobular inflammation, portal inflammation, and giant cell transformation on peri-operative biopsies. The primary outcome was the frequency of native liver survival. A random effects meta-analysis was used. Twenty-eight observational studies were included, 1,171 pediatric patients with BA of whom 631 survived with their native liver. Lower odds of native liver survival in the severe liver fibrosis vs. non-severe liver fibrosis groups were reported (odds ratio [OR], 0.16; 95% confidence interval [CI], 0.08-0.33; I2 =46%). No difference in the odds of native liver survival in the severe bile duct destruction vs. non-severe bile duct destruction groups were reported (OR, 0.17; 95% CI, 0.00-63.63; I2 =96%). Lower odds of native liver survival were documented in the severe cholestasis vs. non-severe cholestasis (OR, 0.10; 95% CI, 0.01-0.73; I2 =80%) and severe lobular inflammation vs. non-severe lobular inflammation groups (OR, 0.02; 95% CI, 0.00-0.62; I2 =69%). There was no difference in the odds of native liver survival in the severe portal inflammation vs. non-severe portal inflammation groups (OR, 0.03; 95% CI, 0.00-3.22; I2 =86%) or between the severe giant cell transformation vs. non-severe giant cell transformation groups (OR, 0.15; 95% CI, 0.00-175.21; I2 =94%). The meta-analysis loosely suggests that the presence of severe liver fibrosis, cholestasis, and lobular inflammation are associated with lower odds of native liver survival in pediatric patients after Kasai.

Project description:Genome-wide association studies (GWASs) have identified a genetic associated between EFEMP1 and biliary atresia (BA). To examine the susceptibility of single nucleotide polymorphisms (SNPs) in EFEMP1 in Thai BA patients, we performed an analysis of the genetic associations and biological interactions with previously reported key SNPs in ADD3, a key gene associated with BA. The study also used high-throughput sequencing to detect novel variants in both genes. In addition, the clinical impact of EFEMP1 SNPs in terms of survival association was also evaluated. The genotypes of 60 BA patients and 179 controls were evaluated using a TaqMan genotyping assay for rs2501577 and rs17095355 in ADD3 and rs6761893 and rs727878 in EFEMP1. The genotype frequencies were analyzed together with the SNP-SNP interactions. Fine mapping by whole-exome sequencing was performed to identify deleterious variants within both genes, and the survival analysis results were analyzed with the EFEMP1 SNPs. The recessive genotypes of rs2501577, rs17095355 and rs6761893 showed significantly higher frequencies in the BA patients than the controls, and a logistic regression showed that minor alleles of those SNPs increased the BA risk by ORs of 1.86, 1.67, and 1.84, respectively. Moreover, the SNP-SNP interference suggested that a combination of recessive alleles from the 2 genes resulted in an additive risk to BA. In addition, rare missense variants in the gene coding sequences were identified in 7 cases. Immunohistochemical studies revealed a pattern of ADD3 downregulation and EFEMP1 overexpression in the bile ducts of BA patients. Patients with the AA genotype of rs6761893 had significantly lower 5-year native liver survival (34.0%) than those with AT/TT (75.0%), with a log-rank p value of 0.041. Variants in EFEMP1 are associated with the occurrence of BA in Thai patients. In addition, these variants have an additive influence on BA risk when combined with ADD3 variants. Moreover, rs6761893 in EFEMP1 was indicative of survival in Thai BA patients.

Project description:Purpose: The hypoxic tumor microenvironment was reported to be involved in different tumorigenesis mechanisms of breast cancer (BC). We aimed to establish a hypoxia-related gene signature to identify a new BC subtype through the clustering analysis and explore potential compounds targeting the BC subtypes. Methods: Gene expression data and clinical features of BC and adjacent non-tumor tissues were downloaded from the Cancer Genome Atlas-Breast cancer (TCGA-BRCA) database. We comprehensively revealed the activity changes of Gene Ontology (GO) biological processes (BP) gene sets in BC by gene set variation analysis (GSVA) and identified three hypoxia-related BC subtypes. We then matched the differentially expressed gene profile of each subtype with the gene profile in CMap database to identify the potential agents targeting the BC subtypes. Results: 562 of Gene Ontology biological processes gene sets significantly correlated with hypoxia score in breast cancer. 969 BC patients were clustered into three subtypes based on the enrichment score of hypoxia-associated gene sets. Subtype 1 patients displayed better survival than subtype 2 and 3. KEGG pathway enrichment analysis of each subtype was performed based on the unique differential expression genes profile. In subtype 1, the upregulated genes were associated with lipid and amino acid metabolism regulation; in subtype 2, the upregulated genes were associated with metabolic energy regulation, while in subtype 3, the upregulated genes were associated with apoptosis and protein process. Using the CMap database, 55, 111 and 63 compounds were identified, targeting subtype 1, 2, and 3, respectively. Conclusion: In this study, novel hypoxia-related subtypes were developed for patients with BC. In addition, biological processes associated with differential expression genes profile and potential therapeutic target compounds were identified in each subtype. The new classification might provide a better understanding of the role of hypoxia in breast cancer and more individualized treatment for patients.

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Gene Expression Signatures Associated With Survival Times of Pediatric Patients With Biliary Atresia Identify Potential Therapeutic Agents.

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Gene Expression Signatures Associated With Survival Times of Pediatric Patients With Biliary Atresia Identify Potential Therapeutic Agents.

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